BAP31 Maintains Breast Cancer Cell Endoplasmic Reticulum Calcium Homeostasis And Apoptosis Resistance Via Binding To SERCA2

Breast cancer is the most common cancertype and leading cause of mortality in women worldwide.The newly discovered cancer/testis antigen BAP31,a molecular chaperone in the endoplasmic reticulum,is involved in many biological processes.However,its function in breast cancer has not been studied yet.In this study,we observed that the expression of BAP31 was higher in breast cancer tissue samples,compared with benign breast tissue samples.We further found that higher levels of BAP31 were associated with worse overall prognosis,and poor survival rate without distant metastasis in breast cancer patients.In addition,the high expression of BAP31 was correlated with higher tumor grade and malignancy.Therefore,we decided to further explore the function and mechanism of BAP31 in breast cancer cell line and mouse model.In this study,we found that BAP31 widely affected the cell functions of breast cancer cells.BAP31 inhibition decreased the proliferation,metastasis,invasion and apoptosis resistance of breast cancer cells.SERCA2,a protein directly bound to BAP31,was identified by protein immunoprecipitation,silver staining and mass spectrometry.SERCA2 is a calcium ion pump and mainly responsible for the transport of calcium ions into the endoplasmic reticulum(ER)lumen against the concentration gradient.It maintains the calcium homeostasis of the cell together with other calcium pumps or channels on the membrane of the endoplasmic reticulum as well as the cell surface.Although the interaction of BAP31 and SERCA2 did not affect either of their protein levels,BAP31 inhibition decreased the endoplasmic reticulum calcium storage.That resulted in long-term ER stress in breast cancer cells.Therefore BAP31 inhibition increased the proportion of apoptosis cells,as well as the proportion of anoikis cells in the condition of loss of adhension.BAP31 inhibition resulted in the loss of apoptotic resistance of breast cancer cells to a certain extent when they grow in situ,and the loss of anoikis resistance after tumor cells having been invaded into peripheral blood.Therefore,the process of primary tumor development and distant metastasis were inhibited.To better simulate this process,human breast cancer cells were injected into the subcutaneous fat pad and tail vein of female nude mice for in vivo experiments and the results were as expected.Taken together,our findings showed that BAP31 directly bound with the endoplasmic reticulum calcium pump,SERCA2.They maintained the endoplasmic reticulum calcium homeostasis,apoptosis resistance and anoikis resistance of breast cancer cells.Thus BAP31 played a key role in the development and distance metastasis of breast cancer,which provided us a potential therapeutic target of breast cancer treatment in the future.